Tadashi Sakane

Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking‑independent lung adenocarcinoma

Patients with smoking-independent lung cancer mainly consist of females, yet the molecular background of this epidemiological feature, other than epidermal growth factor receptor (EGFR) mutation, remains unclear. Several studies have revealed the association between female hormone-associated factors and the prognosis of lung cancer, however the data remain inconsistent. The present study focused on the expression of estrogen receptor (ER)α in order to elucidate this association in smoking-independent lung cancer. Immunohistochemistry staining (IHC) of aromatase, ERα and ERβ was performed against formalin-treated tissues from 38 patients who had never-smoked who underwent complete surgical resection between 2012 and 2013. Among them, adequate RNA of the tumor and adjacent normal lung cancer was extracted from 31 matching deep frozen samples. Considering the IHC results, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of 2 different exons of ERα, exon 6 and exon 7, which are part of the ligand binding domain of ERα, using the Taqman gene expression assay. Extra-nuclear expression of ERα using IHC demonstrated a statistically significant association with pathological invasiveness. RT-qPCR results exhibited a decreased expression of ERα exon 7 in invasive tumor tissues, compared with their adjacent normal tissues. This is consistent with the findings of previous in vitro studies indicating that extra-nuclear ERα were exon 7 splicing variants. No difference was observed in ERα exon 7 expression between normal and tumor tissues in non-invasive lung cancer tissues. When considering the EGFR mutation status, EGFR wild-type lung cancers exhibited decreased ERα exon 7 expression levels compared with EGFR mutated lung cancers. Extra-nuclear expression of ERα, which may represent exon 7 splicing variants of ERα, showed statistical association with pathological invasiveness in smoking-independent lung cancer. The post-translational splicing mechanism of ERα may be involved in the acquired invasiveness of smoking independent lung cancer.

Blastomatoid pulmonary carcinosarcoma: A rare case report and review of the literature: Blastomatoid pulmonary carcinosarcoma

A 65‐year‐old never‐smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X‐ray. Computed tomography (CT) revealed a 5‐cm tumor in segment 6 of her right lung and an enlarged subcarinal lymph node, suggesting metastasis. The lung tumor was diagnosed as adenocarcinoma by a CT‐guided percutaneous needle biopsy. She was referred to our hospital and underwent right lower lobectomy with lymph node dissection (ND2a‐2). A histopathological examination of the tumor showed a biphasic proliferation made of carcinomatous and sarcomatous components. The carcinomatous component consisted of glandular structures of atypical cells that possessed chromatin‐rich nuclear and clear cytoplasm, confirming high‐grade fetal adenocarcinoma. The sarcomatous component consisted of immature spindle cells that differentiated into chondrosarcoma. Immunohistochemically, the glandular structures expressed membranous beta‐catenin, and the ultimate diagnosis was blastomatoid variant of pulmonary carcinosarcoma. She received four courses of cisplatin plus vinorelbine as adjuvant chemotherapy and remained alive with neither recurrence nor distant metastasis at two and a half years after the operation. We experienced a rare case of blastomatoid pulmonary carcinoasarcoma.

Thymothymectomy with pulmonary partial resection using the subxiphoid approach: how to do it?

An open approach by sternotomy is still selected for locally advanced anterior mediastinal tumors. Technical and instrumental improvements to video-assisted thoracic surgery (VATS) have enabled the treatment of anterior mediastinal tumor in the last decade, and the indications of VATS for an anterior mediastinal tumor are thus expanding. Recently, a single-port thymectomy procedure using the subxiphoid approach has gained popularity worldwide because of its low invasiveness. Improvements to the thoracoscopic instruments and the development of a single-port device are expanding the adoption of single-port VATS in the thoracic surgical field, including resection of anterior mediastinal tumors. We, herein, report a case of thymothymectomy with pulmonary partial resection using the subxiphoid approach. This approach is useful for extended operation for anterior mediastinal tumors and provides favorable results regarding postoperative pain and cosmetic outcomes.

Four immunohistochemical assays to measure the PD-L1 expression in malignant pleural mesothelioma

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway are expected to be a novel therapy for combating future increases in numbers of malignant pleural mesothelioma (MPM) patients. However, the PD-L1 expression, which is a predictor of the response to ICIs, is unclear in MPM. We studied the PD-L1 expression using four immunohistochemical assays (SP142, SP263, 28-8 and 22C3) in 32 MPM patients. The PD-L1 expression in tumor cells and immune cells was evaluated to clarify the rate of PD-L1 expression and the concordance among the four assays in MPM. The positivity rate of PD-L1 expression was 53.1% for SP142, 28.1% for SP263, 53.1% for 28-8, and 56.3% for 22C3. Nine cases were positive and 10 were negative for all assays. Discordance among the four assays was found in 13 cases. The concordance rates between SP142 and 22C3 and between 28-8 and 22C3 were the highest (84.4%). The concordance rates between SP263 and the other three assays were low (71.9% to 75.0%). The PD-L1 expression in MPM was almost equivalent for three of the assays. Given the cut-off values set in our study, these findings suggested that these assays, except for SP263, can be used for accurate PD-L1 immunostaining in MPM.

A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma

Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ≥50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs – rather than ICs – were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.

The relationship between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase, excision repair cross‑complementation group 1 and class III β‑tubulin, and the therapeutic effect of S‑1 or carboplatin plus paclitaxel in non‑small‑cell lung cancer

Previous studies have reported that the expressions of specific proteins may predict the efficacy of chemotherapy agents for non-small cell lung cancer (NSCLC) patients. The present study evaluated the expression of proteins hypothesized to be associated with the effect of chemotherapeutic agents in 38 NSCLC patients with pathological stage II and IIIA. The subjects received carboplatin plus paclitaxel (CP) or S-1 as adjuvant chemotherapy following complete resection. The protein expressions evaluated were those of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phsphoribosyltransferase (OPRT), which were suspected to be associated with the effect of S-1 agents, excision repair cross-complementation group 1 (ERCC1), which was suspected to be associated with the effect of platinum-based agents, and class III β-tubulin (TUBB3), which was suspected to be associated with the effect of taxane-based agents. The positive rate of TS was 55.3% (n=21/38), DPD was 57.9% (n=22/38), OPRT was 42.1% (n=16/38), ERCC1 was 47.4% (n=18/38) and TUBB3 was 44.7% (n=17/38). Among the patients who received S-1 adjuvant chemotherapy, TS-negative cases demonstrated a significantly better disease-free survival than positive cases. Thus, TS protein expression may have been a factor that predicted the effect of S-1 agent as adjuvant chemotherapy.

The outcomes of anatomical lung resection for nontuberculous mycobacterial lung disease

Background The number of cases of nontuberculous mycobacterial (NTM) lung disease has been increasing in recent years, and the efficacy of surgical treatment has been recognized. We investigated the clinical characteristics and behavior of NTM lung disease and analyzed the outcomes of surgery. Methods The data of 25 patients who underwent anatomical resection for NTM lung disease in our institution between January 2004 and December 2014 were retrospectively examined. Results The patients included 10 men and 15 women (mean age, 63.1 years). Twenty patients had Mycobacterium avium, and 5 had Mycobacterium intracellular. The indications for lung resection in 20 definitively diagnosed patients included a remaining or worsening lesion despite medical treatment (n=16), massive hemoptysis or bloody sputum (n=5), and prolonged smear positivity (n=1); multiple reasons were allowed. In five cases without a definitive diagnosis, surgery was performed due to the suspicion of lung cancer. The surgical procedures included pneumonectomy, n=4; lobectomy, n=13; and segmentectomy, n=8. Complete resection was achieved in 10 cases (40.0%). Video-assisted thoracoscopic surgery (VATS) was performed in 17 cases (68.0%), especially in 6 of 8 cases (75.0%) that underwent segmentectomy and in 10 of 11 cases (90.9%) that received simple lobectomy. There was one case of hospital mortality. Among the 22 patients who were followed at our institution, relapse occurred in 4 patients, and new infection occurred in 1 patient. NTM lung disease was controlled in 17 patients (77.3%). In the four cases that relapsed, the median relapse-free interval was 29.5 months. Conclusions Surgical resection was a feasible treatment for NTM lung disease and was associated with favorable outcomes, although there was 1 case of hospital mortality. VATS procedures were considered adequate for the treatment of NTM lung disease; however, the surgical indications must be carefully considered.

Pure red cell aplasia associated with thymoma: a report of a single-center experience

Background Pure red cell aplasia (PRCA) associated with thymoma is relatively rare, and relevant reports are limited. We investigated the clinical features and outcomes of PRCA associated with thymoma in this study. Methods A retrospective review of all PRCA patients who underwent surgical resection of thymoma from April 1, 2004, to December 31, 2015, was performed. Results We experienced eight patients with PRCA among 146 patients who underwent surgical resection of thymoma. Extended thymectomy (n=4) and thymectomy (n=4) were performed for thymoma. Regarding the WHO classification of thymoma, the subtypes were type B2 or B3 in seven patients, and the stage of thymoma was advanced in seven patients. Complete resection was achieved macroscopically in only five patients. Recurrence of thymoma occurred in four patients who underwent complete resection. PRCA was diagnosed after surgical resection of thymoma in six patients (range 1-101 months, median 56.5 months). Cyclosporine was used for PRCA in six patients. Pneumonia of treatment-related complications due to cyclosporine occurred in all patients. The follow-up period ranged from 13-147 months (median 54.5 months) after the PRCA diagnosis. Three patients obtained complete remission of anemia by cyclosporine. Although one patient was able to stop taking cyclosporine because of complete remission of anemia, transfusion was needed due to relapse of PRCA. Five patients died, with the main causes of death diagnosed as pneumonia (n=4) and cardiac failure (n=1). Conclusions PRCA associated with thymoma was diagnosed postoperatively in three-quarter of patients. We should be alert for the occurrence of PRCA even after resection of thymoma, especially in patients with incomplete resection or advanced disease. Cyclosporine was effective for PRCA, but treatment-related complications occurred, particularly pneumonia. As treatment for PRCA associated with thymoma and its complications were combined in a complex manner, treating PRCA associated with thymoma can be quite difficult.

Recent advances in video-assisted transthoracic tracheal resection followed by reconstruction under non-intubated anesthesia with spontaneous breathing

Tracheal resection followed by reconstruction is one of the most difficult procedures in the field of thoracic surgery. Right thoracotomy performed via a posterolateral incision is selected for middle and lower tracheal resection under general anesthesia. In order to develop a novel less invasive surgical procedure, it is necessary to devise methods to keep the operating field clear and to use better methods of anesthesia. Thoracic surgeons have attempted to improve surgical techniques, the approach, and methods of anesthesia in order to minimize the trauma to the patient and to reduce the incidence of postoperative complications, including respiratory complications.

Clinicopathological factors influenced the prognosis of surgically resected pulmonary pleomorphic carcinoma

BACKGROUND Pulmonary pleomorphic carcinoma has made an unfavorable prognosis because of its properties of resisting radiation and chemotherapy, and its aggressive growth. The correlation between clinicopathological factors and prognosis about pulmonary pleomorphic carcinoma patients who received its surgical resection has not been clearly identified. METHODS We retrospectively investigated the clinical records of 24 pulmonary pleomorphic carcinoma patients who had a surgical resection from January 2004 to December 2013 at our institute. We examined the correlation between their clinicopathological factors and therapeutic effects including their prognosis. RESULTS The median follow up time was 2.3 years. The 5-year survival was 54.7% and the 5-year progression free survival was 52.4%. In comparison with other tissue types of lung cancer, the prognosis was not so poor even taking into consideration the survival curve including several progression stages. We analyzed the 21 clinicopathological factors in order to clarify the factors connected with the prognosis and disease progression. As a result, we found that both vascular invasion evaluated by immunohistochemistry and lymph node metastasis were connected closely with the overall survival. We found another strong link between the tissue type of epithelial components, vascular invasion evaluated by immunohistochemistry and lymph nodal metastasis with the progression free survival. CONCLUSIONS Pulmonary pleomorphic carcinoma patients with lymph node metastasis and vascular invasion had worse prognosis after their surgical resections. We have to find an effective chemotherapeutic drug or molecular targeted drug.